Therapeutic compounds

ABSTRACT

Compounds comprising or a pharmaceutically acceptable salt or a prodrug thereof are disclosed, wherein a dashed line represents the presence or absence of a bond; and, wherein Y, A, R, D, and n are as described. Methods, compositions, and medicaments related thereto are also disclosed.

CROSS REFERENCE

This is a national stage application under 35 U.S.C. §371 of PCT patentapplication PCT/US09/43700, filed on May 13 2009, which claims thebenefit of U.S. Provisional Patent 61/054,682, filed on May 20, 2008,each of which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspre-surgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

SUMMARY OF THE INVENTION

Disclosed herein are compounds useful in treating glaucoma, inflammatorybowel disease, the stimulation of hair growth, and the stimulation ofthe conversion of vellus hair to terminal hair. The compounds themselvesare disclosed below.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein are compounds of the formula

wherein a dashed line represents the presence or absence of a bond;

Y is

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O;

U¹ is independently hydrogen; OH; O; S; F; Cl; Br; I; CN; or O-alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms;

J¹ and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN; O-alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2, 3, 4, 5, or 6carbon atoms; or CF₃;

Z is S, SO, SO₂, NR, NCOR, or NSO₂R, wherein R is H or C₁₋₆ hydrocarbyl,and

B is aryl or heteroaryl.

Any structure depicted herein, whether alone or presented with otherstructures, is contemplated as an individual embodiment.

Furthermore, for each individual structure presented herein, anembodiment is contemplated which comprises the compound of thestructure, and/or one or more prodrugs of compounds of the structure,and/or one or more pharmaceutically acceptable salts of the compounds ofthe structure.

An embodiment is also contemplated which comprises the compound of thestructure, and/or one or more pharmaceutically acceptable salts of thecompounds of the structure.

An embodiment is also contemplated which comprises the compound of thestructure, and/or one or more prodrugs of compounds of the structure.

Since a dashed line represents the presence or absence of a bond,compounds such as those according to the structures below are possible.

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O.

While not intending to be limiting, A may be —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is replaced with S or O. For example, whilenot intending to limit the scope of the invention in any way, A may be amoiety where S replaces one or two carbon atoms such as one of thefollowing or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be a moiety where O replaces one or two carbon atomssuch as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may have an O replacing one carbon atom and an S replacinganother carbon atom, such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)— whereinAr is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3,or 4, and wherein one CH₂ may be replaced with S or O. In other words,while not intending to limit the scope of the invention in any way,

in one embodiment A comprises 1, 2, 3, or 4 CH₂ moieties and Ar, e.g.—CH₂—Ar—, —(CH₂)₂—Ar—, —CH₂—Ar—CH₂—, —CH₂Ar—(CH₂)₂—, —(CH₂)₂—Ar—(CH₂)₂—,and the like;

in another embodiment A comprises: O; 0, 1, 2, or 3 CH₂ moieties; andAr, e.g., —O—Ar—, Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —O—CH₂—Ar—,—O—CH₂—Ar—(CH₂)₂, and the like; or

in another embodiment A comprises: S; 0, 1, 2, or 3 CH₂ moieties; andAr, e.g., —S—Ar—, Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —S—CH₂—Ar—,—S—CH₂—Ar—(CH₂)₂, —(CH₂)₂—S—Ar, and the like.

In another embodiment, the sum of m and o is 2, 3, or 4 wherein one CH₂may be replaced with S or O.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may bereplaced with S or O.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may bereplaced with S or O.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or heterointerarylene may be substituted orunsubstituted. Unsubstituted interarylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or heterointerarylene has substituents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂-Ph-. While not intending to limit scopeof the invention in any way, substituents may have 4 or less heavyatoms, wherein the heavy atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. Any number of hydrogen atoms required for aparticular substituent will also be included. A substituent must bestable enough for the compound to be useful as described herein. Inaddition to the atoms listed above, a substituent may also have a metalcation or any other stable cation having an atom not listed above if thesubstituent is acidic and the salt form is stable. For example, —OH mayform an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺ salt. Any cation of thesalt is not counted in the “4 or less heavy atoms.” Thus, thesubstituent may be

hydrocarbyl having up to 4 carbon atoms, including alkyl up to C₄,alkenyl, alkynyl, and the like;

hydrocarbyloxy up to C₃;

organic acid such as CO₂H, SO₃H, P(O)(OH)₂, and the like, and saltsthereof;

CF₃;

halo, such as F, Cl, or Br;

hydroxyl;

NH₂ and alkylamine functional groups up to C₃;

other N or S containing substituents such as CN, NO₂, and the like;

and the like.

In one embodiment A is —(CH₂)_(m)-Ph-(CH₂)_(o)— wherein the sum of m ando is 1, 2, or 3, and wherein one CH₂ may be replaced with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂-Ph-OCH₂—. In another embodiment, Ph is attached at the 1 and 3positions, otherwise known as m-interphenylene, such as when A has thestructure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph- wherein one CH₂ may be replaced with S or O.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be replaced with S orO; or A is —(CH₂)₂-Ph-.

In other embodiments, A has one of the following structures, where Y isattached to the aromatic or heteroaromatic ring.

In another embodiment A is —CH₂OCH₂Ar.

In another embodiment A is —CH₂SCH₂Ar.

In another embodiment A is —(CH₂)₃Ar.

In another embodiment A is —CH₂—O—(CH₂)₄.

In another embodiment A is —CH₂S(CH₂)₄.

In another embodiment A is —(CH₂)₆—.

In another embodiment A is cis —CH₂CH═CH—(CH₂)₃—.

In another embodiment A is —CH₂C≡C—(CH₂)₃—.

In another embodiment A is —S(CH₂)3S(CH₂)₂—.

In another embodiment A is —(CH₂)₄OCH₂—.

In another embodiment A is cis —CH₂CH═CH—CH₂OCH₂—.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is —(CH₂)₂S(CH₂)3-.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is —CH₂—O—(CH₂)₄—.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

In another embodiment A is (3-methylphenoxy)methyl.

In another embodiment A is (4-but-2-ynyloxy)methyl.

In another embodiment A is 2-(2-ethylthio)thiazol-4-yl.

In another embodiment A is 2-(3-propyl)thiazol-5-yl.

In another embodiment A is 3-methoxymethyl)phenyl.

In another embodiment A is 3-(3-propylphenyl.

In another embodiment A is 3-methylphenethyl.

In another embodiment A is 4-(2-ethyl)phenyl.

In another embodiment A is 4-phenethyl.

In another embodiment A is 4-methoxybutyl.

In another embodiment A is 5-(methoxymethyl)furan-2-yl.

In another embodiment A is 5-(methoxymethyl)thiophen-2-yl.

In another embodiment A is 5-(3-propyl)furan-2-yl.

In another embodiment A is 5-(3-propyl)thiophen-2-yl.

In another embodiment A is 6-hexyl.

In another embodiment A is (Z)-6-hex-4-enyl.

Compounds according to the each of the structures depicted below arepossible.

U¹ is independently O; S; F; Cl; Br; I; CN; or O-alkyl having 1, 2, 3,4, 5 or 6 carbon atoms.

In one embodiment, U¹ is hydrogen.

In one embodiment, U¹ is OH.

In one embodiment, U¹ is O.

In one embodiment, U¹ is S.

In one embodiment, U¹ is F.

In one embodiment, U¹ is Cl.

In one embodiment, U¹ is Br.

In one embodiment, U¹ is I.

In one embodiment, U¹ is CN.

In one embodiment, U¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

J¹ and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN; O-alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2, 3, 4, 5, or 6carbon atoms; or CF₃.

In one embodiment, J¹ is hydrogen.

In one embodiment, J¹ is F.

In one embodiment, J¹ is Cl.

In one embodiment, J¹ is Br.

In one embodiment, J¹ is I.

In one embodiment, J¹ is O.

In one embodiment, J¹ is OH.

In one embodiment, J¹ is CN.

In one embodiment, J¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

In one embodiment, J¹ is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

In one embodiment, J¹ is CF₃.

In one embodiment, J² is hydrogen.

In one embodiment, J² is F.

In one embodiment, J² is Cl.

In one embodiment, J² is Br.

In one embodiment, J² is I.

In one embodiment, J² is O.

In one embodiment, J² is OH.

In one embodiment, J² is CN.

In one embodiment, J² is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

In one embodiment, J² is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

In one embodiment, J² is CF₃.

Thus, compounds according to the structures shown below are possible.

Z is S, SO, SO₂, NR, NCOR, or NSO₂R, wherein R is H or C₁₋₆ hydrocarbyl.

Thus, compounds such as shown below are possible.

In one embodiment, Z is S.

In another embodiment, Z is NH.

In another embodiment, Z is SO.

In another embodiment, Z is SO₂.

In another embodiment, Z is NCH₃.

In another embodiment, Z is NC₂H₅.

In another embodiment, Z is NC₃H₇.

In another embodiment, Z is NC₄H₉.

In another embodiment, Z is NC₅H₁₁.

In another embodiment, Z is NC₆H₁₃.

In another embodiment, Z is N-phenyl.

In another embodiment, Z is NSO₂CH₃.

In another embodiment, Z is NCOCH₃.

B is aryl or heteroaryl.

Aryl is an aromatic ring or ring system such as phenyl, naphthyl,biphenyl, and the like.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.one or more ring carbons are substituted by N, O, and/or S. While notintending to be limiting, examples of heteroaryl include thienyl,pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl, indolyl, andthe like.

A substituent of aryl or heteroaryl may have up to 20 non-hydrogen atomseach in any stable combination and as many hydrogen atoms as necessary,wherein the non-hydrogen atoms are C, N, O, S, P, F, Cl, Br, and/or I inany stable combination. However, the total number of non-hydrogen atomson all of the substituents combined must also be 20 or less. Asubstituent must be sufficiently stable for the compound to be useful asdescribed herein. In addition to the atoms listed above, a substituentmay also have a metal cation or other stable cation having an atom notlisted above if the substituent is acidic and the salt form is stable.For example, —OH may form an —O⁻Na⁺ salt or CO₂H may form a CO₂ ⁻K⁺salt. Any cation of the salt is not counted in the 20 non-hydrogenatoms. Thus, while not intending to limit the scope of the invention inany way, a substituent may be:

hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen suchas alkyl, alkenyl, alkynyl, and the like, including linear, branched orcyclic hydrocarbyl, and combinations thereof;

hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,O-cyclohexyl, etc, up to 19 carbon atoms;

other ether substituents such as CH₂OCH₃, (CH₂)₂OCH(CH₃)₂, and the like;

thioether substituents including S-hydrocarbyl and other thioethersubstituents;

hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH₂OH, C(CH₃)₂OH,etc, up to 19 carbon atoms;

nitrogen substituents such as NO₂, CN, and the like, including

amino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like;

carbonyl substituents, such as CO₂H, ester, amide, and the like;

halogen, such as chloro, fluoro, bromo, and the like

fluorocarbyl, such as CF₃, CF₂CF₃, etc.;

phosphorous substituents, such as PO₃ ²⁻, and the like;

sulfur substituents, including S-hydrocarbyl, SH, SO₃H, SO₂-hydrocarbyl,SO₃-hydrocarbyl, and the like.

Substituted aryl or heteroaryl may have as many substituents as the ringor ring system will bear, and the substituents may be the same ordifferent. Thus, for example, an aryl ring or a heteroaryl ring may besubstituted with chloro and methyl; methyl, OH, and F; CN, NO₂, andethyl; and the like including any conceivable substituent or combinationof substituent possible in light of this disclosure.

Substituted aryl or substituted heteroaryl also includes a bicyclic orpolycyclic ring system wherein one or more rings are aromatic and one ormore rings are not. For example, indanonyl, indanyl, indanolyl,tetralonyl, and the like are substituted aryl and are also substitutedphenyl. For this type of polycyclic ring system, an aromatic orheteroaromatic ring, not a non-aromatic ring, must be attached to theremainder of the molecule, i.e. the part of the molecule that is not B.In other words, in any structure depicting —B herein, where — is a bond,the bond is a direct bond to an aromatic ring.

Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,

-   wherein R is hydrogen or C1-10 hydrocarbyl.-   Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,

-   wherein R is hydrogen or C1-10 hydrocarbyl.-   Another embodiment is a compound according to the structure

or a pharmaceutical salt thereof, or a prodrug thereof,

-   wherein R is hydrogen or C1-10 hydrocarbyl.-   Another embodiment is a compound according to the structure

“C1-10” hydrocarbyl is hydrocarbyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 carbon atoms.

Hydrocarbyl is a moiety consisting of only carbon and hydrogen, andincludes, but is not limited to alkyl, alkenyl, alkynyl, and the like,and in some cases aryl, and combinations thereof.

Alkyl is hydrocarbyl having no double or triple bonds including:

linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl,and the like;

branched alkyl such as isopropyl, branched butyl isomers (i.e.sec-butyl, tert-butyl, etc), branched pentyl isomers (i.e. isopentyl,etc), branched hexyl isomers, and higher branched alkyl fragments;

cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc.; and

alkyl fragments consisting of both cyclic and noncyclic components,whether linear or branched, which may be attached to the remainder ofthe molecule at any available position including terminal, internal, orring carbon atoms.

Alkenyl is hydrocarbyl having one or more double bonds including

linear alkenyl, branched alkenyl, cyclic alkenyl, and combinationsthereof in analogy to alkyl.

Alkynyl is hydrocarbyl having one or more triple bonds including linearalkynyl, branched alkynyl, cyclic alkynyl and combinations thereof inanalogy to alkyl.

Aryl is an unsubstituted or substituted aromatic ring or ring systemsuch as phenyl, naphthyl, biphenyl, and the like. Aryl may or may not behydrocarbyl, depending upon whether it has substituents withheteroatoms.

Arylalkyl is alkyl which is substituted with aryl. In other words alkylconnects aryl to the remaining part of the molecule. Examples are—CH₂-Phenyl, —CH₂—CH₂-Phenyl, and the like. Arylalkyl may or may not behydrocarbyl, depending upon whether the aryl portion has substituentswith heteroatoms.

Unconjugated dienes or polyenes have one or more double bonds which arenot conjugated. They may be linear, branched, or cyclic, or acombination thereof.

Combinations of the above are also possible.

In another embodiment, B is substituted or unsubstituted phenyl.

In another embodiment, B is substituted or unsubstituted thienyl.

In another embodiment, B is substituted or unsubstituted naphthyl.

In another embodiment, B is substituted or unsubstituted furyl.

In another embodiment, B is substituted or unsubstituted pyridinyl.

In another embodiment, B is substituted or unsubstituted benzothienyl.

In another embodiment, B is substituted or unsubstituted indanyl.

In another embodiment, B is substituted or unsubstituted tetralonyl.

In another embodiment, B has 1, 2, 3, 4, or 5 substituents, wherein eachsubstituent has one or more carbon, fluorine, chlorine, bromine, oxygen,sulfur, or atoms; and wherein all substituents taken together consist of0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; 0, 1, 2, 3, 4, 5, 6, 7,8 or 9 fluorine atoms; 0, 1, 2 or 3 chlorine atoms, 0, 1, 2 or 3 bromineatoms, 0, 1, 2 or 3 oxygen atoms; 0, 1, 2, or 3 sulfur atoms; 0, 1, 2,or 3 nitrogen atoms.

In another embodiment, B has 1, 2, 3, 4, or 5 substituents, wherein eachsubstituent has one or more carbon, fluorine, chlorine, bromine, oroxygen atoms; and wherein all substituents taken together consist of 0,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; 0, 1, 2, 3, 4, 5, 6, 7, 8or 9 fluorine atoms; 0, 1, 2 or 3 chlorine atoms, 0, 1, 2 or 3 bromineatoms, and 0, 1, 2 or 3 oxygen atoms.

In another embodiment, B has a substituent of the formulaC_(a)H_(b)O_(c); wherein a is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9, b is 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19; and cis 0, 1, 2, or 3.

In another embodiment, B has 1, 2, 3, or 4 alkyl substituents having 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

In another embodiment, B has a hydroxyalkyl substituent having 0, 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 1 or 2 hydroxy moieties.

In another embodiment, B has an alkyl substituent having 0, 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 carbon atoms.

In another embodiment, B has 1, 2, 3, or 4 halogen substituents.

In another embodiment, B has 1, 2, 3, or 4 chloro substituents.

In another embodiment, B has 1 chloro substituent.

In another embodiment, B has 2 chloro substituents.

In another embodiment, B has 1, 2, 3, or 4 trifluoromethyl substituents.

In another embodiment, B has 1, 2, or 3 trifluoromethyl substituents.

In another embodiment, B has 1 trifluoromethyl substituent.

In another embodiment, B has 2 trifluoromethyl substituents.

In another embodiment, B has a hydroxyl substituent.

Examples of useful moieties for B are depicted below. Each isindividually contemplated as an embodiment.

In the above embodiments, x is 5, 6, or 7, and y+z is 2x+1.

In one embodiment, x is 5 and y+z is 11.

In another embodiment, x is 6 and y+z is 13.

In another embodiment, x is 7 and y+z is 15.

In one embodiment, said compound is not

wherein U² is OH or H.

In another embodiment, said compound is not

wherein J³ is O or OH and U² is OH or H.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C1 (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administered isdependent on the therapeutic effect or effects desired, on the specificmammal being treated, on the severity and nature of the mammal'scondition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds may be inthe range of about 0.5 or about 1 to about 100 mg/kg/day.

Ophthalmic Applications

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle   0-40 tonicity adjustor   1-10 buffer 0.01-10 pHadjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,co-solvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

For treatment of diseases affecting the eye including glaucoma, thesecompounds can be administered topically, periocularly, intraocularly, orby any other effective means known in the art.

Applications for Baldness

In one embodiment, the compounds disclosed herein can be useful in thetreatment of baldness and/or hair loss. Alopecia (baldness) is adeficiency of either normal or abnormal hair, and is primarily acosmetic problem in humans. It is a deficiency of terminal hair, thebroad diameter, colored hair that is readily seen. However, in the socalled bald person, although there is a noticeable absence of terminalhair, the skin does contain vellus hair, which is a fine colorless hairwhich may require microscopic examination to determine its presence.This vellus hair is a precursor to terminal hair.

The compounds described herein can be used to stimulate, such as theconversion of vellus hair to growth as terminal hair, as well asincreasing the rate of growth of terminal hair. The utility of thecompounds described herein for the simulation of hair growth wasdiscovered as follows.

In the course of treating patients having glaucoma, treatment may onlybe appropriate in one eye. Within the course of daily practice, it wasdiscovered that a patient who had been treated with bimatoprost, aprostaglandin analogue, developed lashed that were longer, thicker, andfuller in the treated eye than in the non-treated eye. On examination,the difference was found to be very striking. The lashes were longer andhad a fuller, denser appearance in the treated eye. The lash appearanceon the lids of the treated eyes would have appeared quite attractive ifit represented a bilateral phenomenon. As a result of its asymmetricnature, the long lashes on one side could be construed as disturbingfrom a cosmetic standpoint. A systemic examination was preformed as aresult of the asymmetric phenomenon. It soon became apparent that thisaltered appearance was not an isolated finding. Comparison of the lidsof patients who were taking bimatoprost in only one eye revealed subtlechanges in the lashed and adjacent hairs of the bimatoprost-treated sidein several patients. Definite differences could be identified to varyingdegrees in the lashes and adjacent hairs of all patients who were takingthe drug on a unilateral basis for longer than 6 months.

The changes in the lashes were apparent on gross inspection in severalpatients once attention was focused on the issue. In those with lightcolored hair and lashes, the differences were only seen easily with theaid of the high magnification and lighting capabilities of the slit lampbiomicroscope. In the course of glaucoma follow-up examination,attention is generally immediately focused on the eye itself. As aresult of the high power magnification needed only one eye is seen at atime and the eye is seen at a high enough power that the lashes are notin focus. At these higher powers, any lash asymmetry between the twoeyes is not likely to be noticed except by careful systematic comparisonof the lashes and adjacent hairs of the eyelids of the two eyes.

Observed parameters leading to the conclusion that more robust hairgrowth occurred in the treatment area following administration of theprostaglandin analogue were multiple. They included increased length oflashed, increased number of lashes along the normal lash line, increasedthickness and luster of lashes, increased auxiliary lash-like terminalhair in transitional areas adjacent to areas of normal lash growth,increased auxiliary lash-like terminal hairs at the medial and lateralcanthal area, increased pigmentation of the lashes, increased numbers,increased length, as well as increased luster, and thickness of finehair on the skin of the adjacent lid, and finally, increasedperpendicular angulation of lashes and lash-like terminal hairs. Theconclusion that hair growth is stimulated by prostaglandin analoguessuch as bimatoprost is thus supported not by evidence of a difference ina single parameter, but is based on multiple parameters of hairappearance in treated versus control areas in many subjects.

The compounds described herein are prostaglandin analogues and thereforehave similar activities as bimatoprost, contain structural similarities,and therefore are expected to stimulate hair growth and stimulation ofthe conversion of vellus hair to terminal hair. In one embodiment, thecompounds described herein and their prodrugs can be used for thestimulation of hair growth. As used herein, hair growth includes hairassociated with the scalp, eyebrows, eyelids, beard, and other areas ofthe skin of animals.

In one embodiment, the compound is mixed with a dermatologicallycompatible vehicle or carrier. The vehicle, which may be employed forpreparing compositions as described herein, may comprise, for example,aqueous solutions such as e.g., physiological salines, oil solutions, orointments. The vehicle furthermore may contain dermatologicallycompatible preservatives such as e.g., benzalkonium chloride,surfactants like e.g., polysorbate 80, liposomes or polymers, forexample, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone andhyaluronic acid; these may be used for increasing the viscosity.Furthermore, it is also possible to use soluble or insoluble druginserts when the drug is to be administered.

In one embodiment, dermatological compositions can be formulated fortopical treatment for the stimulation of hair growth which comprises aneffective hair growth simulating amount of one or more compounds asdefined above and a dermatologically compatible carrier. Effectiveamounts of the active compounds may be determined by one of ordinaryskill in the art, but will vary depending on the compound employed,frequency of application and desired result. The compound will generallyrange from about 0.0000001 to about 50% by weight of the dermatologicalcomposition. Preferably, the compound will range from about 0.001 toabout 50% by weight of total dermatological composition, more preferablyfrom about 0.1 to about 30% by weight of the composition.

In one embodiment, the application of the present compounds forstimulation of hair growth finds applications in mammalian species,including both humans and animals. In humans, the compounds describedherein can be applied for example, to the scalp, face beard, head, pubicarea, upper lip, eyebrows, and eyelids. In animal raised for theirpelts, e.g., mink, the compounds described herein can be applied overthe entire surface of the body to improve the overall pelt forcommercial reasons. The process can also be used for cosmetic reasons inanimals, e.g., applied to the skin of dogs and cats having bald patchesdue to mange or other diseases causing a degree of alopecia.

The pharmaceutical compositions contemplated for the stimulation of hairgrowth include pharmaceutical compositions suited for topical and localaction. The term “topical” as employed herein relates to the use of acompound, as described herein, incorporated in a suitable pharmaceuticalcarrier, and applied at the site of thinning hair or baldness forexertion of local action. Accordingly, such topical compositions includethose pharmaceutical forms in which the compound is applied externallyby direct contact with the skin to be treated. Conventionalpharmaceutical forms for this purpose include ointments, liniments,creams, shampoos, lotions, pastes, jellies, sprays, aerosols, and thelike, and may be applied in patches or impregnated dressings dependingon the part of the body to be treated. The term “ointment” embracesformulations (including creams) having oleaginous, water-soluble andemulsion-type bases, e.g., petrolatum, lanolin, polyethylene glycols, aswell as mixtures of these.

Typically, the compounds can be applied repeatedly for the sustainedperiod of time topically on the part of the body to be treated, forexample, the eyelids, eyebrows, skin or scalp. The preferred dosageregimen will generally involve regular, such as daily, administrationfor a period of treatment of at least one month, more preferably atleast three months, and most preferably, at least six months.

For topical use on the eyelids or eyebrows, the active compounds can beformulated in aqueous solutions, creams, ointments, or oils exhibitingphysologicla acceptable osmolarity by addition of pharmaceuticallyacceptable buffers and salts. such formulations may or may not,depending on the dispenser, contain preservatives such as benzalkoniumchloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids andphenylmercuric salts such as nitrate, chloride, acetate, and borate, orantioxidants, as well as additives like EDTA, sorbitol, boric acid andthe like as additives. Furthermore, particularly aqueous solutions maycontain viscosity increasing agents such as polysaccharides, e.g.,methylcellulose, mucopolysaccharides, e.g., hyaluronic acid andchondroitin sulfate, or poly alcohol, e.g., polyvinylalcohol. Variousslow releasing gels and matricies may also be employed as well assoluble and insoluble ocular inserts, for instance, based on substancesforming in situ gels. Depending on the actual formation and compound tobe used, various amounts of the drug and different dose regimens may beemployed. Typically, the daily amount of compound for treatment of theeyelid may be about 0.1 ng to about 100 mg per eyelid.

For topical use on the skin and scalp, the compound can beadvantageously formulated using ointments, creams, liniments or patchesas a carrier of the active ingredient. Also, these formulations may ormay not contain preservatives, depending on the dispenser and nature ofuse. Such preservatives include those mentioned above, and methyl-,propyl-, or butyl-parahydroxybenzoic acid, betain, chlorhexidine,benzalkonium chloride, and the like. Various matricies for the slowrelease delivery may also be used. Typically, the dose to be applied onthe scalp is in the range of about 0.1 ng to about 100 mg per day, morepreferably about 1 ng to about 10 mg per day, and most preferably about10 ng to about 1 mg per day depending on the compound and theformulation. To achieve the daily amount of medication depending on theformulation, the compound may be administered once or several timesdaily with or without antioxidants.

A person of ordinary skill in the art understands the meaning of thestereochemistry associated with the hatched wedge/solid wedge structuralfeatures. For example, an introductory organic chemistry textbook(Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company1987, p. 63) states “a wedge indicates a bond coming from the plane ofthe paper toward the viewer” and the hatched wedge, indicated as a“dashed line”, “represents a bond receding from the viewer.”

COMPOUND EXAMPLES

The following are hypothetical examples of useful compounds:

Compound Example 1

A compound of the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

wherein a dashed line represents the presence or absence of a bond;

Y is

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O;

U¹ is independently hydrogen; OH; O; S; F; Cl; Br; I; CN; or O-alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms;

J¹ and J² are independently hydrogen; F; Cl, Br; I; O; OH; CN; O-alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms; alkyl having 1, 2, 3, 4, 5, or 6carbon atoms; or CF₃;

Z is S, SO, SO₂, NR, NCOR, or NSO₂R, wherein R is H or C₁₋₆ hydrocarbyl,and

B is aryl or heteroaryl;

wherein said compound is not

wherein U² is OH or H.

Compound Example 2

The compound according to compound example 1 of the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Compound Example 3

The compound according to compound example 1 having the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Compound Example 4

The compound according to compound example 1 having the formula

or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

Compound Example 5

The compound according to any one of compound examples 1 to 4 Wherein Ais (3-methylphenoxy)methyl.

Compound Example 6

The compound according to any one of compound examples 1 to 4 wherein Ais (4-but-2-ynyloxy)methyl.

Compound Example 7

The compound according to any one of compound examples 1 to 4 wherein Ais 2-(2-ethylthio)thiazol-4-yl.

Compound Example 8

The compound according to any one of compound examples 1 to 4 wherein Ais 2-(3-propyl)thiazol-5-yl.

Compound Example 9

The compound according to any one of compound examples 1 to 4 wherein Ais 3-(methoxymethyl)phenyl.

Compound Example 10

The compound according to any one of compound examples 1 to 4 wherein Ais 3-(3-propyl)phenyl.

Compound Example 11

The compound according to any one of compound examples 1 to 4 wherein Ais 3-methylphenethyl.

Compound Example 12

The compound according to any one of compound examples 1 to 4 wherein Ais 4-(2-ethyl)phenyl.

Compound Example 13

The compound according to any one of compound examples 1 to 4 wherein Ais 4-phenethyl.

Compound Example 14

The compound according to any one of compound examples 1 to 4 wherein Ais 4-methoxybutyl.

Compound Example 15

The compound according to any one of compound examples 1 to 4 wherein Ais 5-(methoxymethyl)furan-2-yl.

Compound Example 16

The compound according to any one of compound examples 1 to 4 wherein Ais 5-(methoxymethyl)thiophen-2-yl.

Compound Example 17

The compound according to any one of compound examples 1 to 4 wherein Ais 5-(3-propyl)furan-2-yl.

Compound Example 18

The compound according to any one of compound examples 1 to 4 wherein Ais 5-(3-propyl)thiophen-2-yl.

Compound Example 19

The compound according to any one of compound examples 1 to 4 wherein Ais 6-hexyl.

Compound Example 20

The compound according to any one of compound examples 1 to 4 wherein Ais (Z)-6-hex-4-enyl.

Compound Example 21

The compound according to any one of compound examples 1, 2 and 5 to 20having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 22

The compound according to any one of compound examples 1 and 5 to 20having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 23

The compound according to any one of compound examples 1 and 4 to 20having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 24

The compound according to any one of compound examples 1 and 4 to 20having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 25

The compound according to any one of compound examples 1 and 4 to 20having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 26

The compound according to any one of compound examples 1 and 4 to 20having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 27

The compound according to any one of compound examples 1 and 4 to 20having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 28

The compound according to any one of compound examples 1 and 4 to 20having the formula

or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Compound Example 29

The compound according to any one of compound examples 1 and 5 to 20wherein U¹ is O.

Compound Example 30

The compound according to any one of compound examples 1 and 5 to 20wherein U¹ is S.

Compound Example 31

The compound according to any one of compound examples 1 and 5 to 20wherein U¹ is F.

Compound Example 32

The compound according to any one of compound examples 1 and 5 to 20wherein U¹ is Cl.

Compound Example 33

The compound according to any one of compound examples 1 and 5 to 20wherein U¹ is Br.

Compound Example 34

The compound according to any one of compound examples 1 and 5 to 20wherein U¹ is I.

Compound Example 35

The compound according to any one of compound examples 1 and 5 to 20wherein U¹ is CN.

Compound Example 36

The compound according to any one of compound examples 1 and 5 to 20wherein U¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

Compound Example 37

The compound according to any one of compound examples 1, 5 to 20, and29 to 36, wherein J¹ is hydrogen.

Compound Example 38

The compound according to any one of compound examples 1, 5 to 20, and29 to 36, wherein J¹ is F.

Compound Example 39

The compound according to any one of compound examples 1, 5 to 20, and29 to 36, wherein J¹ is Cl.

Compound Example 40

The compound according to any one of compound examples 1, 5 to 20, and29 to 36, wherein J¹ is Br.

Compound Example 41

The compound according to any one of compound examples 1, 5 to 20, and29 to 36, wherein J¹ is I.

Compound Example 42

The compound according to any one of compound examples 1, 5 to 20, and29 to 36, wherein J¹ is O.

Compound Example 43

The compound according to any one of compound examples 1, 5 to 20, and29 to 36, wherein J¹ is OH.

Compound Example 44

The compound according to any one of compound examples 1, 5 to 20, and29 to 36, wherein J¹ is CN.

Compound Example 45

The compound according to any one of compound examples 1, 5 to 20, and29 to 36, wherein J¹ is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

Compound Example 46

The compound according to any one of compound examples 1, 5 to 20, and29 to 36, wherein J¹ is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

Compound Example 47

The compound according to any one of compound examples 1, 5 to 20, and29 to 36, wherein J¹ is CF₃.

Compound Example 48

The compound according to any one of compound examples 1, 5 to 20, and29 to 47 wherein J² is hydrogen.

Compound Example 49

The compound according to any one of compound examples 1, 5 to 20, and29 to 47 wherein J² is F.

Compound Example 50

The compound according to any one of compound examples 1, 5 to 20, and29 to 47 wherein J² is Cl.

Compound Example 51

The compound according to any one of compound examples 1, 5 to 20, and29 to 47 wherein J² is Br.

Compound Example 52

The compound according to any one of compound examples 1, 5 to 20, and29 to 47 wherein J² is I.

Compound Example 53

The compound according to any one of compound examples 1, 5 to 20, and29 to 47 wherein J² is O.

Compound Example 54

The compound according to any one of compound examples 1, 5 to 20, and29 to 47 wherein J² is OH.

Compound Example 55

The compound according to any one of compound examples 1, 5 to 20, and29 to 47 wherein J² is CN.

Compound Example 56

The compound according to any one of compound examples 1, 5 to 20, and29 to 47 wherein J² is O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

Compound Example 57

The compound according to any one of compound examples 1, 5 to 20, and29 to 47 wherein J² is alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

Compound Example 58

The compound according to any one of compound examples 1, 5 to 20, and29 to 47 wherein J² is CF₃.

Compound Example 59

The compound according to any one of compound examples 1 to 58 wherein Bis substituted or unsubstituted phenyl.

Compound Example 60

The compound according to any one of compound examples 1 to 58 wherein Bis substituted or unsubstituted thienyl.

Compound Example 61

The compound according to any one of compound examples 1 to 58 wherein Bis substituted or unsubstituted naphthyl.

Compound Example 62

The compound according to any one of compound examples 1 to 58 wherein Bis substituted or unsubstituted furyl.

Compound Example 63

The compound according to any one of compound examples 1 to 58 wherein Bis substituted or unsubstituted pyridinyl.

Compound Example 64

The compound according to any one of compound examples 1 to 58 wherein Bis substituted or unsubstituted benzothienyl.

Compound Example 65

The compound according to any one of compound examples 1 to 58 wherein Bis substituted or unsubstituted indanyl.

Compound Example 66

The compound according to any one of compound examples 1 to 58 wherein Bis substituted or unsubstituted tetralonyl.

Compound Example 67

The compound according to any one of compound examples 1 to 58 wherein Bhas 1, 2, 3, 4, or 5 substituents, wherein each substituent has one ormore carbon, fluorine, chlorine, bromine, or oxygen atoms; and whereinall substituents taken together consist of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9or 10 carbon atoms; 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms; 0, 1,2 or 3 chlorine atoms, 0, 1, 2 or 3 bromine atoms, and 0, 1, 2 or 3oxygen atoms.

Compound Example 68

The compound according to any one of compound examples 1 to 58 wherein Bhas a substituent of the formula C_(a)H_(b)O_(c); wherein a is 0, 1, 2,3, 4, 5, 6, 7, 8 or 9, b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18 or 19; and c is 0, 1, 2, or 3.

Compound Example 69

The compound according to any one of compound examples 1 to 58 wherein Bhas 1, 2, 3, or 4 alkyl substituents having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbon atoms.

Compound Example 70

The compound according to any one of compound examples 1 to 58 wherein Bhas a hydroxyalkyl substituent having 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms and 1 or 2 hydroxy moieties.

Compound Example 71

The compound according to any one of compound examples 1 to 58 wherein Bhas an alkyl substituent having 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms.

Compound Example 72

The compound according to any one of compound examples 1 to 58 wherein Bhas 1, 2, 3, or 4 halogen substituents.

Compound Example 73

The compound according to any one of compound examples 1 to 58 wherein Bhas 1, 2, 3, or 4 chloro substituents.

Compound Example 74

The compound according to any one of compound examples 1 to 58 wherein Bhas 1 chloro substituent.

Compound Example 75

The compound according to any one of compound examples 1 to 58 wherein Bhas 2 chloro substituents.

Compound Example 76

The compound according to any one of compound examples 1 to 58 wherein Bhas 1, 2, 3, or 4 trifluoromethyl substituents.

Compound Example 77

The compound according to any one of compound examples 1 to 58 wherein Bhas 1, 2, or 3 trifluoromethyl substituents.

Compound Example 78

The compound according to any one of compound examples 1 to 58 wherein Bhas 1 trifluoromethyl substituent.

Compound Example 79

The compound according to any one of compound examples 1 to 58 wherein Bhas 2 trifluoromethyl substituents.

Compound Example 80

The compound according to any one of compound examples 1 to 58 wherein Bhas a hydroxyl substituent.

Compound Example 81

The compound according to any one of compound examples 1 to 59 wherein Bis unsubstituted phenyl.

Compound Example 82

The compound according to any one of compound examples 1 to 59 wherein Bis 3,5-dichlorophenyl.

Compound Example 83

The compound according to any one of compound examples 1 to 59 wherein Bis 3,5-di(trifluoromethyl)phenyl.

Compound Example 84

The compound according to any one of compound examples 1 to 59 wherein Bis 2-chlorophenyl.

Compound Example 85

The compound according to any one of compound examples 1 to 59 wherein Bis 3-chlorophenyl.

Compound Example 86

The compound according to any one of compound examples 1 to 59 wherein Bis 4-chlorophenyl.

Compound Example 87

The compound according to any one of compound examples 1 to 59 wherein Bis 3-(trifluoromethyl)phenyl.

Compound Example 88

The compound according to any one of compound examples 1 to 59 wherein Bis 3-isopropylphenyl.

Compound Example 89

The compound according to any one of compound examples 1 to 59 wherein Bis 3-tert-butylphenyl.

Compound Example 90

The compound according to any one of compound examples 1 to 59 wherein Bis 3-hydroxyphenyl.

Compound Example 91

The compound according to any one of compound examples 1 to 59 wherein Bis 3-methoxyphenyl.

Compound Example 92

The compound according to any one of compound examples 1 to 59 wherein Bis 3-(benzoyloxy)phenyl.

Compound Example 93

The compound according to any one of compound examples 1 to 59 wherein Bis 2,3-dimethylphenyl.

Compound Example 94

The compound according to any one of compound examples 1 to 59 wherein Bis 3,4-dimethylphenyl.

Compound Example 95

The compound according to any one of compound examples 1 to 59 wherein Bis 2,4-dimethylphenyl.

Compound Example 96

The compound according to any one of compound examples 1 to 59 wherein Bis 2,5-dimethylphenyl.

Compound Example 97

The compound according to any one of compound examples 1 to 59 wherein Bis 3,5-dimethylphenyl.

Compound Example 98

The compound according to any one of compound examples 1 to 59 wherein Bis 2,6-dimethylphenyl.

Compound Example 99

The compound according to any one of compound examples 1 to 59 wherein Bis 3-(hydroxymethyl)phenyl.

Compound Example 100

The compound according to any one of compound examples 1 to 59 wherein Bis 3-(1-hydroxyethyl)phenyl.

Compound Example 101

The compound according to any one of compound examples 1 to 59 wherein Bis 3-(1-hydroxy-2-methylpropyl)phenyl.

Compound Example 102

The compound according to any one of compound examples 1 to 59 wherein Bis 2-(hydroxymethyl)phenyl.

Compound Example 103

The compound according to any one of compound examples 1 to 59 wherein Bis 4-(hydroxymethyl)-3,5-dimethylphenyl.

Compound Example 104

The compound according to any one of compound examples 1 to 59 wherein Bis 4-(methoxymethyl)-3,5-dimethylphenyl.

Compound Example 105

The compound according to any one of compound examples 1 to 59 wherein Bis 3-(1-hydroxybutyl)phenyl.

Compound Example 106

The compound according to any one of compound examples 1 to 59 wherein Bis 4-(1-methoxybutyl)phenyl.

Compound Example 107

The compound according to any one of compound examples 1 to 59 wherein Bis 4-(1-hydroxybutyl)phenyl.

Compound Example 108

The compound according to any one of compound examples 1 to 59 wherein Bis 4-(2-hydroxyethyl)phenyl.

Compound Example 109

The compound according to any one of compound examples 1 to 59 wherein Bis 3-(2-hydroxyethyl)phenyl.

Compound Example 110

The compound according to any one of compound examples 1 to 59 wherein Bis 2-(2-hydroxyethyl)phenyl.

Compound Example 111

The compound according to any one of compound examples 1 to 59 wherein Bis 4-(2-hydroxyethyl)-3,5-dimethylphenyl.

Compound Example 112

The compound according to any one of compound examples 1 to 59 wherein Bis 3-(1-hydroxyhexyl)phenyl.

Compound Example 113

The compound according to any one of compound examples 1 to 59 wherein Bis 3-(acetoxymethyl)-5-chlorophenyl.

Compound Example 114

The compound according to any one of compound examples 1 to 59 wherein Bis 1-oxo-2,3-dihydro-1H-inden-4-yl.

Compound Example 115

The compound according to any one of compound examples 1 to 59 wherein Bis 1-hydroxy-2,3-dihydro-1H-inden-4-yl.

Compound Example 116

The compound according to any one of compound examples 1 to 59 wherein Bis 5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl.

Compound Example 117

The compound according to any one of compound examples 1 to 59 wherein Bis 3-(1-hydroxy-2-phenylethyl)phenyl.

Compound Example 118

The compound according to any one of compound examples 1 to 59 wherein Bis 4-(2-phenylpropan-2-yl)phenyl.

Compound Example 119

The compound according to any one of compound examples 1 to 59 wherein Bis naphthalen-2-yl.

Compound Example 120

The compound according to any one of compound examples 1 to 59 wherein Bis naphthalen-1-yl.

Compound Example 121

The compound according to any one of compound examples 1 to 59 wherein Bis 4-chloronaphthalen-1-yl.

Compound Example 122

The compound according to any one of compound examples 1, 5 to 20, and37 to 121 wherein U¹ is hydrogen.

Compound Example 123

The compound according to any one of compound examples 1, 5 to 20, and37 to 121 wherein U¹ is OH.

Compound Example 124

The compound according to compound example 1 wherein said compound isnot

wherein J³ is O or OH and U² is OH or H.

Compound Example 125

The compound according to any one of compound examples 1 to 123 whereinZ is S.

Compound Example 126

The compound according to any one of compound examples 1 to 123 whereinZ is NH.

Compound Example 127

The compound according to any one of compound examples 1 to 123 whereinZ is NCH₃.

Compound Example 128

The compound according to any one of compound examples 1 to 123 whereinZ is SO.

Compound Example 129

The compound according to any one of compound examples 1 to 123 whereinZ is SO₂.

Compound Example 130

The compound according to any one of compound examples 1 to 123 whereinZ is NSO₂CH₃.

Compound Example 131

The compound according to any one of compound examples 1 to 123 whereinZ is NCOCH₃.

Composition Example

A composition comprising a compound according to any one of compoundexamples 1 to 131, wherein said composition is a liquid which isophthalmically acceptable.

Medicament Examples

Use of a compound according to any one of compound examples 1 to 131 inthe manufacture of a medicament for the treatment of glaucoma or ocularhypertension in a mammal.

Use of a compound according to any one of compound examples 1 to 131 inthe manufacture of a medicament for the treatment of baldness in aperson.

Use of a compound according to any one of compound examples 1 to 131 inthe manufacture of a medicament for the stimulation of hair growth in aperson.

Use of a compound according to any one of compound examples 1 to 131 inthe manufacture of a medicament for the stimulation of the conversion ofvellus hair to terminal hair in a person.

A medicament comprising a compound according to any one of compoundexamples 1 to 131, wherein said composition is a liquid which isophthalmically acceptable.

Method Example

A method comprising administering a compound according to any one ofcompound examples 1 to 131 to a mammal for the treatment of glaucoma orocular hypertension.

Kit Example

A kit comprising a composition comprising compound according to any oneof compound examples 1 to 131, a container, and instructions foradministration of said composition to a mammal for the treatment ofglaucoma or ocular hypertension.

“Treatment,” “treat,” or any other form of these words as used hereinare intended to mean use in the diagnosis, cure, mitigation, treatment,or prevention of disease in man or other animals.

Synthetic Methods

Synthetic Example 1

Step 1. Mesylation of 1 to Give 2

Triethylamine (26 μL, 0.19 mmol) and methanesulfonyl chloride (12 μL,0.15 mmol) were added sequentially to a solution of(Z)-7-[(1R,2S,3R,5R)-5-chloro-2-hydroxymethyl-3-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-hept-5-enoicacid allyl ester (1, see U.S. Provisional Patent Application No.60/757,696, filed Jan. 10, 2006, which is incorporated by referenceherein; 50 mg, 0.125 mmol) in CH₂Cl₂ (1.25 mL) at 0° C. The reactionmixture was allowed to warm to room temperature. After 3 d at roomtemperature, the reaction mixture was partitioned between saturatedaqueous NaHCO₃ (5 mL) and CH₂Cl₂ (5 mL). The phases were separated andthe aqueous phase was extracted with CH₂Cl₂ (2×5 mL). The combinedextracts were washed with brine (5 mL), dried (MgSO₄), filtered andconcentrated in vacuo to afford crude mesylate 2 which was used withoutfurther purification.

Step 2. Reaction of 2 to Give Thiol 3

A solution of 3,5-dichlorobenzenethiol (78 mg, 0.44 mmol) in DMF (3 mL)was added to a suspension of sodium hydride (60 wt % in oil, 17 mg, 0.43mmol) in DMF (1 mL) at room temperature. After 30 min at roomtemperature, a solution of mesylate 2 (crude, ˜0.125 mmol) in THF (1.2mL) was added. After 1 h, the reaction mixture was heated at 35° C.After 18 h at 35° C., the reaction mixture was partitioned betweenaqueous HCl (0.1 N, 20 mL) and EtOAc (20 mL). The phases were separatedand the organic phase was washed with H₂O (15 mL) and brine (15 mL),dried (MgSO₄), filtered and concentrated in vacuo. Purification of thecrude residue by flash column chromatography on 40 g of silica gel (100%hexane→100% EtOAc, gradient) afforded 20 mg (29% over two steps) ofthiol 3.

Step 3. Deprotection of 3 to Give 4

Pyridinium p-toluenesulfonate (PPTs, 1 mg, 0.004 mmol) was added to asolution of 3 (20 mg, 0.035 mmol) in methanol (0.35 mL) at roomtemperature under nitrogen. The solution was heated at 40° C. overnight,then cooled and concentrated in vacuo. Purification of the crude residueby flash column chromatography on 4 g of silica gel (100% hexane→100%EtOAc, gradient) afforded 11 mg (65%) of alcohol 4.

Step 4. Saponification of 4 to Give 5

Lithium hydroxide (92 μL of a 1.0 M aqueous solution, 0.092 mmol) wasadded to a solution of ester 4 (11 mg, 0.023 mmol) in THF (0.1 mL).After stirring overnight at room temperature, the reaction mixture waspartitioned between aqueous HCl (0.1 N, 5 mL) and EtOAc (5 mL). Thephases were separated and the aqueous phase was extracted with EtOAc(2×5 mL). The combined extracts were dried (MgSO₄), filtered andconcentrated in vacuo to afford 8 mg (79%) of compound (5).

Step 5. Conversion of 5 to 6

Triethylamine and ethyl chloroformate are added sequentially to asolution of compound 5 in CH₂Cl₂ at room temperature. After 2.5 h,triethylamine and ethylene glycol are added. After stirring overnight atroom temperature, the reaction mixture is partitioned between H₂O andCH₂Cl₂. The phases are separated and the aqueous phase is exteractedwith CH₂Cl₂ (2×). The combined organic phase is washed with 1 N HCl thendried (MgSO₄), filtered and concentrated in vacuo. Purification of theresidue by flash column chromatography on silica gel (10% CH₃OH/CH₂Cl₂)affords compound 6.

Conversion of 5 to 7

Triethylamine and ethyl chloroformate are added sequentially to asolution of compound 5 in CH₂Cl₂ at room temperature. After 2.5 h,triethylamine and 4-(2-hydroxyethyl)-morphine are added. After stirringovernight at room temperature, the reaction mixture is partitionedbetween H₂O and CH₂Cl₂. The phases are separated and the aqueous phaseis exteracted with CH₂Cl₂ (2×). The combined organic phase is washedwith 1 N HCl then dried (MgSO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(10% CH₃OH/CH₂Cl₂) affords compound 7.

Synthetic Example 2

Step 1. Oxidation of 1 to Give 8

DMSO (47 μL, 0.66 mmol) was added to a solution of oxalyl chloride (26μL, 0.29 mmol) in CH₂Cl₂ (0.25 mL) at −78° C. After 15 min, a solutionof alcohol 1 (125 mg, 0.31 mmol) in CH₂Cl₂ (0.5 mL+0.5 mL rinse) wasadded. After 15 min at −78° C., triethylamine (272 L, 1.95 mmol) wasadded and the reaction was allowed to warm to room temperature. After 1h at room temperature the reaction mixture was partitioned betweensaturated aqueous NaHCO₃ (3 mL) and CH₂Cl₂ (5 mL). The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (2×5 mL). Thecombined extracts were dried (MgSO₄), filtered and concentrated invacuo. Purification of the crude residue by flash column chromatographyon silica gel (30% EtOAc/hexane) afforded 90 mg (72%) of aldehyde 8.

Step 2. Reduction Amination to Give 9

3,5-Dichloroaniline (57 mg, 0.35 mmol) was added to a solution ofaldehyde 8 (90 mg, 0.23 mmol) in CH₂Cl₂ (1.75 mL) at room temperature.After 1 h, sodium triacetoxyborohydride (74 mg, 0.35 mmol) was added.After 18 h at room temperature, the reaction mixture was partitionedbetween saturated aqueous NaHCO₃ (5 mL) and CH₂Cl₂ (5 mL). The phaseswere separated and the aqueous phase was extracted with CH₂Cl₂ (2×5 mL).The combined extracts were washed with brine (5 mL), dried (MgSO₄),filtered and concentrated in vacuo. Purification of the crude residue byflash column chromatography on 4 g of silica gel (100% hexane 100%EtOAc, gradient) afforded 120 mg of an inseparable mixture of desiredproduct 9 and 3,5-dichloroaniline which was used without furtherpurification.

Step 3. Acylation of 9 to Give 10

Pyridine (17 μL, 0.21 mmol) and acetyl chloride (14 μL, 0.20 mmol) wereadded sequentially to a solution of impure amine 9 (˜32 mg, ˜0.059 mmol)in CH₂Cl₂ (0.1 mL) at 0° C. The reaction mixture was allowed to warm toroom temperature. After 18 h at room temperature the reaction mixturewas partitioned between saturated aqueous NaHCO₃ (2 mL) and CH₂Cl₂ (5mL). The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (5 mL). The combined extracts were washed with brine (2 mL),dried (MgSO₄), filtered and concentrated in vacuo. Purification of thecrude residue by flash column chromatography on 4 g of silica gel (100%hexane→100% EtOAc, gradient) afforded 22 mg (64%) of acetate 10.

Step 4. Deprotection of 10 to Give 11

PPTs (1 mg, 0.004 mmol) was added to a solution of 10 (22 mg, 0.037mmol) in methanol (0.38 mL) at room temperature under nitrogen. Thesolution was heated at 40° C. overnight, then cooled and concentrated invacuo. Purification of the crude residue by flash column chromatographyon 4 g of silica gel (100% hexane 100% EtOAc, gradient) afforded 19 mg(quant.) of alcohol 11.

Step 5. Deprotection of 11 to Give 12

Pyrrolidine (3 μL, 0.036 mmol) andtetrakis(triphenylphosphine)palladium(0) (2 mg, 0.0017 mmol) were addedto a solution of allyl ester 11 (19 mg, 0.038 mmol) in CH₂Cl₂ (0.4 mL).After stirring overnight at room temperature, the reaction mixture waspartitioned between aqueous HCl (1 N, 5 mL) and CH₂Cl₂ (5 mL). Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(2×5 mL). The combined extracts were dried (MgSO₄), filtered andconcentrated in vacuo. Purification of the crude residue by flash columnchromatography on 4 g of silica gel (2×, 10% MeOH/CH₂Cl₂) afforded 5 mg(29%) of compound 12.

Synthetic Example 3

Step 6. Lithium hydroxide (21 μL of a 1.0 M aqueous solution, 0.021mmol) was added to a solution of acetate 12 (2 mg, 0.004 mmol) in THF(0.2 mL). After stirring 3 d at room temperature, the reaction mixturewas partitioned between aqueous HCl (1.0 N, 2 mL) and EtOAc (2 mL). Thephases were separated and the aqueous phase was extracted with EtOAc (2mL). The combined extracts were dried (MgSO₄), filtered and concentratedin vacuo to afford 1 mg (55%) of compound 13.

Step 7A. Conversion of 13 to 14

Triethylamine and ethyl chloroformate are added sequentially to asolution of compound 13 in CH₂Cl₂ at room temperature. After 2.5 h,triethylamine and ethylene glycol are added. After stirring overnight atroom temperature, the reaction mixture is partitioned between H₂O andCH₂Cl₂. The phases are separated and the aqueous phase is exteractedwith CH₂Cl₂ (2×). The combined organic phase is washed with 1 N HCl thendried (MgSO₄), filtered and concentrated in vacuo. Purification of theresidue by flash column chromatography on silica gel (10% CH₃OH/CH₂Cl₂)affords compound 14.

Step 7B. Conversion of 13 to 15

Triethylamine and ethyl chloroformate are added sequentially to asolution of compound 13 in CH₂Cl₂ at room temperature. After 2.5 h,triethylamine and 4-(2-hydroxyethyl)-morphine are added. After stirringovernight at room temperature, the reaction mixture is partitionedbetween H₂O and CH₂Cl₂. The phases are separated and the aqueous phaseis exteracted with CH₂Cl₂ (2×). The combined organic phase is washedwith 1 N HCl then dried (MgSO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(10% CH₃OH/CH₂Cl₂) affords compound 15.

Synthetic Example 4

Step 1. Reduction Amination to Give 17

Sodium triacetoxyborohydride (132 mg, 0.62 mmol) was added in oneportion to a solution of 3,5-dichloroaniline (101 mg, 0.63 mmol) wasadded to a solution of aldehyde 16 (see U.S. Provisional PatentApplication No. 60/947,904, filed Jul. 3, 2007, which is incorporated byreference herein, 130 mg, 0.31 mmol) in CH₂Cl₂ (3.1 mL) at roomtemperature. After 3 d at room temperature, the reaction mixture waspartitioned between saturated aqueous NaHCO₃ (5 mL) and CH₂Cl₂ (10 mL).The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (2×10 mL). The combined organic phase was dried (MgSO₄), filteredand concentrated in vacuo. Purification of the crude residue bychromatography on 12 g of silica gel (100% hexane→100% EtOAc, gradient)afforded 100 mg (57%) of desired product 17.

Step 4. Deprotection of 17 to Give 18

PPTs (1 mg, 0.004 mmol) was added to a solution of 17 (30 mg, 0.053mmol) in methanol (0.5 mL) at room temperature under nitrogen. Thesolution was heated at 40° C. for 18 h, then cooled and concentrated invacuo. Purification of the crude residue by chromatography on 4 g ofsilica gel (100% hexane→100% EtOAc, gradient) afforded 20 mg (78%) ofalcohol 18.

Step 5. Saponification of 18 to Give 19

Lithium hydroxide (0.20 mL of a 1.0 M aqueous solution, 0.20 mmol) wasadded to a solution of ester 18 (20 mg, 0.042 mmol) in THF (0.2 mL).After stirring at 40° C. for 18 h, the reaction mixture was cooled andpartitioned between aqueous HCl (0.1 N, 5 mL) and EtOAc (5 mL). Thephases were separated and the aqueous phase was extracted with EtOAc(2×5 mL). The combined extracts were washed with brine (5 mL), dried(MgSO₄), filtered and concentrated in vacuo. Purification of the cruderesidue by chromatography on 4 g of silica gel (100% hexane→100% EtOAc,gradient) afforded 4 mg (21%) of compound 19.

Step 6. Compounds 20a and 20b

Compounds 20a and 20b were made from compound 19 according to step 5 ofexample 1.

Synthetic Example 5

Step 1. Mesylation of 21 to Give 22

Triethylamine (25 μL, 0.18 mmol) and methanesulfonyl chloride (11 L,0.14 mmol) were added sequentially to a solution of alcohol 21 (see U.S.patent application Ser. No. 11/764,929 filed Jun. 19, 2007, which isincorporated by reference herein, 50 mg, 0.12 mmol) in CH₂Cl₂ (1.2 mL)at 0° C. The reaction mixture was allowed to warm to room temperature.After 3 h at room temperature, the reaction mixture was partitionedbetween saturated aqueous NaHCO₃ (5 mL) and CH₂Cl₂ (5 mL). The phaseswere separated and the aqueous phase was extracted with CH₂Cl₂ (2×5 mL).The combined extracts were washed with water (5 mL) and brine (5 mL),dried (MgSO₄), filtered and concentrated in vacuo to afford crudemesylate 22 which was used without further purification.

Step 2. Reaction of 22 to Give Thiol 23

Sodium hydride (60 wt % in oil, 17 mg, 0.42 mmol) was added to asolution of 3,5-dichlorobenzenethiol (75 mg, 0.42 mmol) in DMF (4 mL) inDMF (1 mL) at room temperature. After 30 min at room temperature, asolution of mesylate 17 (crude, ˜0.12 mmol) in THF (1.2 mL) was addedvia syringe and the reaction mixture was heated at 60° C. After 18 h at60° C., the reaction mixture was cooled and partitioned between water(10 mL) and EtOAc (20 mL). The phases were separated and the aqueousphase was extracted with EtOAc (2×10 mL). The combined organic phase waswashed brine (15 mL), dried (MgSO₄), filtered and concentrated in vacuo.Purification of the crude residue by chromatography on 12 g of silicagel (100% hexane→100% EtOAc, gradient) afforded 10 mg (14% over twosteps) of thiol 23.

Step 3. Deprotection of 23 to Give 24

PPTs (4.3 mg, 0.017 mmol) was added to a solution of 23 (10 mg, 0.017mmol) in methanol (0.17 mL) at room temperature under nitrogen. Thesolution was heated at 40° C. overnight, then cooled and concentrated invacuo. Purification of the crude residue by chromatography on 4 g ofsilica gel (100% hexane→100% EtOAc, gradient) afforded 8 mg (94%) ofalcohol 24.

Step 4. Saponification of 24 to Give 25

In accordance with the procedures of example 4, step 5, ester 19 (8 mg,0.016 mmol) was converted into 6 mg (77%) of compound 25.

Step 5. Compounds 26a and 26b

Compounds 26a and 26b were made from compound 25 according to step 5 ofexample 1.

Synthetic Example 6

Step 1. Oxidation of 27 to Give 28

A solution of sodium period ate (9 mg, 0.042 mmol) in water (0.2 mL) wasadded to a solution of thiol 27 (10 mg, 0.020 mmol) in MeOH (0.2 mL).After stirring at room temperature overnight, the reaction mixture wasdried (MgSO₄), filtered and concentrated in vacuo. Purification of thecrude residue by preparative thin layer chromatography on 4 g of silicagel (10% MeOH/CH₂Cl₂) afforded 3 mg (29%) of sulfoxide 28.

Step 2. Saponification of 28 to Give 29

Lithium hydroxide (0.05 mL of a 1.0 M aqueous solution, 0.05 mmol) wasadded to a solution of ester 28 (3 mg, 0.0059 mmol) in THF (0.05 mL) ina one dram vial and the vial was fitted with a screw top cap. Afterstirring room temperature for 5 d, the reaction mixture acidified withaqueous HCl (1.0 N, 1 mL) and extracted with CH₂Cl₂ (5 mL). The organicphase was dried (MgSO₄), filtered and concentrated in vacuo.Purification of the crude residue by preparative thin layerchromatography on 4 g of silica gel (10% MeOH/CH₂Cl₂) afforded 1 mg(34%) of compound 29.

Step 3. Compounds 30a and 30b

Compounds 30a and 30b were made from compound 29 according to step 5 ofexample 1.

Synthetic Example 7

Step 1. Reaction of 22 to Give Thiol 31

Sodium hydride (60 wt % in oil, 115 mg, 2.88 mmol) was added to asolution of 3,5-difluorbenzenethiol (421 mg, 2.88 mmol) in DMF (20 mL)at room temperature. After 30 min at room temperature, a solution ofmesylate 22 (crude, prepared from 21 (300 mg, 0.72 mmol) in accordancewith the procedures of example 5, step 1, ˜0.72 mmol) in THF (7.2 mL)was added via syringe and the reaction mixture was heated at 40° C.After 3 d at 40° C., the reaction mixture was cooled and partitionedbetween aqueous HCl (1.0 N, 10 mL) and EtOAc (50 mL). The phases wereseparated and the aqueous phase was extracted with EtOAc (2×10 mL). Thecombined organic phase was washed water (50 mL) and brine (50 mL), dried(MgSO₄), filtered and concentrated in vacuo to afford crude thiol 31which was used without further purification.

Step 2. Deprotection of 31 to Give 32

PPTs (18 mg, 0.072 mmol) was added to a solution of thiol 31 (crude,˜0.72 mmol) in methanol (24 mL) at room temperature under nitrogen. Thesolution was heated at 40° C. overnight, then cooled and concentrated invacuo. Purification of the crude residue by chromatography on 12 g ofsilica gel (100% hexane→100% EtOAc, gradient) afforded 7 mg (2%) of purealcohol 32 and 125 mg of 32 contaminated with an impurity.

Step 3. Saponification of 32 to Give 33

Ester 32 (7 mg, 0.015 mmol) was converted into 4 mg (59%) of compound 33in accordance with the procedures of example 4, step 5, with thefollowing modifications: the extraction was carried out with CH₂Cl₂instead of EtOAc and the chromatography gradient was CH₂Cl₂→10%MeOH/CH₂Cl₂.

Step 4. Compounds 34a and 34b

Compounds 34a and 34b were made from compound 33 according to step 5 ofexample 1.

The α-chain A may be modified may be varied by following or adaptingprocedures found in U.S. Provisional Patent Application No. 60/805,285,which is expressly incorporated by reference herein, wherein an analogof the Corey lactone is used as the precursor to a Wittig reaction toinstall all the atoms of the α-chain; other Wittig reactions and thepreparation of the requisite phosphonates are described by Collect.Czech. Chem. Commun. 1994, 58, 138-148, and Collect. Czech. Chem.Commun. 1994, 59, 2533-2544. Alternatively, the intermediate Coreylactone analog may be reduced to the corresponding primary alcohol,which may then be manipulated by methods known in the art to compoundsbearing a heteroatom at the 5th (by alkylation of the alcohol or thederived thiol), 4th (by lengthening the chain by one atom (e.g. byhomologation via the corresponding aldehyde)) or 6th (by shortening thechain by one atom (e.g. by ozonolysis of an enol ether derived from thecorresponding aldehyde)) atom from the acid terminus.

Different J¹, J², and U¹ substituents may be obtained by following oradapting procedures found in the following documents, all of which areexpressly incorporated by reference herein:

-   U.S. Provisional Patent Application No. 60/805,285;-   U.S. Provisional Patent Application No. 60/746,391, filed on May 4,    2006;-   U.S. Provisional Patent Application No. 60/744,236 filed on Apr. 4,    2006;-   U.S. Provisional Patent Application No. 60/746,386 filed on May 4,    2006; and-   U.S. Provisional Patent Application No. 60/747,835, filed on May 22,    2006

Analogs of 3,5-dichloroaniline may be obtained commercially, or preparedfrom commercially available nitroaryl compounds by reduction. Otheraromatic (or heteroaromatic) amines may be prepared from thecorresponding aryl (or heteroaryl) halide or sulfonate by usingbenzophenone imine and following or adapting procedures described byBuchwald, et al. (e.g. J. Org. Chem. 2006, 71, 430-433 and TetrahedronLett. 1997, 38, 6367-6370). Alternatively, the intermediatehydroxymethyl moiety (in compounds such as 1 and its analogs) may beconverted to the corresponding primary amine, for example, via asulfonate intermediate reacting with sodium azide, followed by reductionto a primary amine. This amine may then be arylated (or heteroarylated)via the Buchwald procedure described above.

Analogs of 3,5-dichlorobenzenethiol may be obtained commercially. Otheraromatic (or heteroaromatic) sulfides may be prepared from thecorresponding aryl (or heteroaryl) halide or sulfonate and a silyl-SH oralkyl-SH analog (followed by desilylation or dealkylation to reveal therequisite thiol) by following or adapting procedures described byBuchwald (e.g. Tetrahedron 2004, 60, 7397-7403) and Hartwig (e.g. J. Am.Chem. Soc. 2006, 128, 2180-2181). Alternatively, the nucleophilicaromatic substitution of NaSH with an appropriate aryl or heteroarylhalide may be accomplished by adapting methods known in the art (e.g.see Peach, in Patai, “The Chemistry of the Thiol Group,” pt. 2, pp735-744, Wiley, New York, 1974). In another alternative approach, theintermediate hydroxymethyl moiety (in compounds such as 1 and itsanalogs) may be converted to the corresponding thiol (e.g. via asulfonate intermediate reacting with sodium thioacetate, followed bydeacylation). This thiol then may be arylated (or heteroarylated) onsulfur using an appropriate aryl (or heteroaryl) halide or sulfonate(see Buchwald and Hartwig references above).

Oxidation of the sulfur atom to either to the sulfoxide or the sulfoneanalog may be readily accomplished by methods known in the art.

The following compounds can be useful according to the presentdescription.

The compounds disclosed herein are believed to be selectiveprostaglandin EP₂ agonists, and are thus useful for the treatment ofglaucoma, ocular hypertension, and other diseases or conditions.

Treatment Examples

The following are hypothetical examples demonstrating how a person maybe treated with the compounds disclosed herein.

An aqueous liquid containing 0.1% of H1 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

An aqueous liquid containing 0.1% of H2 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

An aqueous liquid containing 0.1% of H3 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

An aqueous liquid containing 0.1% of H4 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

An aqueous liquid containing 0.1% of H5 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

An aqueous liquid containing 0.1% of H6 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

An aqueous liquid containing 0.1% of H7 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

An aqueous liquid containing 0.1% of H8 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

An aqueous liquid containing 0.1% of H9 is given topically to the eye ofa person suffering from elevated intraocular pressure. A few hours afteradministration, the person's intraocular pressure is reduced. The dropis administered twice a day, and pressure remains low for as long as thetreatment is continued.

An aqueous liquid containing 0.1% of H10 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H11 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H12 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H13 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H14 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H15 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H16 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H17 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H18 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H19 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H20 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H21 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H22 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H23 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H24 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H25 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H26 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H27 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H28 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H29 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H30 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H31 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H32 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H33 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H34 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H35 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H36 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H37 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H38 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H39 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H40 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H41 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H42 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H43 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H44 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H45 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H46 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H47 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H48 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H49 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H50 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H51 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H52 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H53 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H54 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H55 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H56 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H57 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H58 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H59 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H60 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H61 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H62 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H63 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H64 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H65 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H66 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H67 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H68 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H69 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H70 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H71 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H72 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H73 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H74 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H75 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H76 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H77 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H78 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H79 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H80 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H81 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H82 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H83 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H84 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H85 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H86 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H87 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H88 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H89 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H90 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H91 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H92 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H93 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H94 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H95 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H96 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H97 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H98 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H99 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H100 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H101 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H102 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H103 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H104 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H105 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H106 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H107 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H108 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H109 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H110 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H111 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H112 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H113 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H114 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H115 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H116 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H117 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H118 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H119 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H120 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H121 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H122 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H123 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H124 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H125 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H126 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H127 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H128 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H129 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H130 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H131 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H132 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H133 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H134 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H135 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H136 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H137 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H138 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H139 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H140 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H141 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H142 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H143 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H144 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H145 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H146 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H147 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

An aqueous liquid containing 0.1% of H148 is given topically to the eyeof a person suffering from elevated intraocular pressure. A few hoursafter administration, the person's intraocular pressure is reduced. Thedrop is administered twice a day, and pressure remains low for as longas the treatment is continued.

In Vivo Examples

Title compounds H145 and H146 from above are tested in vivo to test itsability to reduce intraocular pressure. Compound H145 is tested innormotensive dogs. The intraocular pressure (IOP) decreases frombaseline. This compound is also tested in laser-induced hypertensivemonkeys, the IOP decreases from baseline.

Compound H146 is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

Compound H147 is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

Compound H148 is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the claims.

1. A compound of the formula

or a pharmaceutically acceptable salt thereof; wherein a dashed linerepresents the presence or absence of a bond; Y is

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be replaced by S or O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)—wherein Ar is interarylene or heterointerarylene, the sum of m and o is1, 2, 3, or 4, and wherein one CH₂ may be replaced by S or O; U¹ isindependently hydrogen; OH; O; S; F; Cl; Br; I; CN; or O-alkyl having 1,2, 3, 4, 5 or 6 carbon atoms; J¹ and J² are independently hydrogen; F;Cl, Br; I; O; OH; CN; O-alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms; or CF₃; Z is S, SO, SO₂,NR, NCOR, or NSO₂R, wherein R is H or C₁₋₆ hydrocarbyl, and B is aryl orheteroaryl.
 2. The compound according to claim 1, wherein said compoundhas the formula

or a pharmaceutically acceptable salt thereof.
 3. The compound accordingto claim 1, wherein said compound has the formula

or a pharmaceutically acceptable salt thereof.
 4. The compound accordingto claim 1, wherein said compound has the formula

or a pharmaceutically acceptable salt thereof.
 5. The compound accordingto claim 1, wherein said compound has the formula

or a pharmaceutically acceptable salt thereof.
 6. The compound accordingto claim 1, wherein said compound has the formula

or a pharmaceutically acceptable salt thereof.
 7. The compound accordingto claim 1, wherein said compound has the formula

or a pharmaceutically acceptable salt thereof.
 8. The compound accordingto claim 1, wherein said compound has the formula

or a pharmaceutically acceptable salt thereof.
 9. The compound accordingto claim 1, wherein said compound has the formula

or a pharmaceutically acceptable salt thereof.
 10. The compoundaccording to claim 1, wherein said compound has the formula

or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 1, wherein said compound has the formula

or a pharmaceutically acceptable salt thereof.
 12. The compoundaccording to claim 1, wherein said compound has the formula

or a pharmaceutically acceptable salt thereof.
 13. A method of treatingbaldness comprising administering to a subject in need thereof atherapeutically effective amount of a compound according to claim
 1. 14.A compound selected from